CN113321720A - Antigenic peptide related to liver cancer driver gene mutation and application thereof - Google Patents

Antigenic peptide related to liver cancer driver gene mutation and application thereof Download PDF

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CN113321720A
CN113321720A CN202110594226.9A CN202110594226A CN113321720A CN 113321720 A CN113321720 A CN 113321720A CN 202110594226 A CN202110594226 A CN 202110594226A CN 113321720 A CN113321720 A CN 113321720A
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liver cancer
gene mutation
antigenic peptide
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driver gene
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CN113321720B (en
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郝冰娜
李许峰
蔡睿
赵环
罗夫辛克纳吉
张积仁
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Shenzhen New Target Biotechnology Co ltd
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Abstract

The invention discloses an antigenic peptide related to liver cancer driver gene mutation, wherein the liver cancer driver gene is at least two of CDKN2A, ERBB4, HNF1A, NFE2L2, NTRK3, LRP1B, PREX2, ZFHX3 and ZNF 521; the sequences of the antigenic peptides are at least two of SEQ No. 1-17; the application of the antigenic peptide, the antigenic peptide is used for inducing and generating specific cytotoxic T cell clone; the antigen peptide has high affinity with MHC I molecules on DC cells, can effectively stimulate and induce to generate specific cytotoxic T lymphocytes, can be used for immune elimination of tumor cells with liver cancer related driver gene mutation, and has good treatment potential.

Description

Antigenic peptide related to liver cancer driver gene mutation and application thereof
Technical Field
The invention relates to an antigenic peptide related to liver cancer driver gene mutation and application thereof, belonging to the technical field of biological medicines.
Background
Liver cancer, a malignant tumor of the liver, can be divided into primary and secondary types. The primary liver malignant tumor originates from the epithelium or mesenchymal tissue of the liver, and the former is called primary liver cancer, which is a malignant tumor with high incidence and great harm in China.
The treatment method comprises operations, hepatic artery ligation, hepatic artery chemoembolization, radio frequency, freezing, laser, microwave, chemotherapy, radiotherapy and the like. Biological treatment, and traditional Chinese medicine treatment of liver cancer is also widely applied.
With the understanding of the nature of the immune response, the concept of cellular immunity has been proposed to effectively prevent the development of various cancers by selectively destroying tumor cells through the unique mutations of tumors using the body's natural defense system.
With the understanding of the nature of tumor-driving gene mutation and personalized precise immune response, a personalized and customized tumor-driving gene mutation-associated peptide antigen is provided as a new concept of tumor-specific new antigen immune cell therapy, and natural T cell immune defense systems of human bodies are induced to selectively destroy tumor-driving gene mutation cells through the unique tumor-driving gene mutation-associated antigen, so that various cancers are effectively prevented from happening, and the technical field is evaluated as ten technical innovation research fields in 2019 of the United states.
However, because of the technical requirements of multidisciplinary, high-technology and multi-platform cooperative research, the antigen peptide related to liver cancer driver gene mutation cannot be systematically found and a relatively complete peptide library is established, so that a therapeutic agent with excellent effect and the like cannot be formed.
Disclosure of Invention
In order to overcome the defects of the prior art, the first objective of the present invention is to provide an antigenic peptide related to liver cancer driver gene mutation, which has high affinity with MHC I molecules on DC cells, can effectively stimulate and induce the generation of specific Cytotoxic T Lymphocytes (CTLs), can be used for the immune clearance of tumor cells related to liver cancer driver gene mutation, and has good therapeutic potential.
The second purpose of the invention is to provide an application of the antigenic peptide related to the liver cancer driver gene mutation.
The first purpose of the invention can be achieved by adopting the following technical scheme: an antigenic peptide related to liver cancer driver gene mutation, wherein the liver cancer driver gene is at least two of CDKN2A, ERBB4, HNF1A, NFE2L2, NTRK3, LRP1B, PREX2, ZFHX3 and ZNF 521.
Wherein, the sequences of the antigenic peptides related to the liver cancer driving gene mutation are at least two of SEQ No. 1-17.
The second purpose of the invention can be achieved by adopting the following technical scheme: the application of the antigenic peptide related to the liver cancer driver gene mutation is to use the antigenic peptide related to the liver cancer driver gene mutation for inducing and generating specific cytotoxic T cell clone.
Or, the application of the antigenic peptide related to the liver cancer driving gene mutation, the antigenic peptide related to the liver cancer driving gene mutation is used for preparing the human body immunological activity regulator capable of inducing the generation of specific cytotoxic T cell clone.
Or, the application of the antigenic peptide related to the liver cancer driver gene mutation is to use the antigenic peptide related to the liver cancer driver gene mutation in the preparation of cell culture solution for preventing and interfering the mutation of at least two genes of CDKN2A, ERBB4, HNF1A, NFE2L2, NTRK3, LRP1B, PREX2, ZFHX3 and ZNF 521.
Or, the application of the antigenic peptide related to the liver cancer driver gene mutation, wherein the antigenic peptide related to the liver cancer driver gene mutation is used for preparing a liver cancer risk intervention therapeutic agent.
The invention carries out comprehensive research from the specific cancer as the starting point, specifically researches the generation mechanism of the liver cancer, realizes the elimination of liver cancer cells with mutation of liver cancer driving genes CDKN2A, ERBB4, HNF1A, NFE2L2, NTRK3, LRP1B, PREX2, ZFHX3 and ZNF521, can inhibit the growth of tumor cells and prevent the generation of the liver cancer. The immunological research proves that the principle that CD8 positive T lymphocyte CTL plays cellular immunity is as follows: CTL cells are activated by recognizing antigen peptides bound to MHC-I molecules, and the activated CTL can kill corresponding target cells to exert an immune surveillance effect.
Compared with the prior art, the invention has the beneficial effects that:
1. the antigenic peptide (neoantigen) related to the liver cancer driver gene mutation refers to an antigenic peptide which is expressed by tumor cells and can activate T cells; through high-throughput gene sequencing and data analysis, individual somatic cell mutations of the tumor of a patient are found, antigen peptides related to driving gene mutations are screened out to serve as targets, and the targets are subjected to in vitro chemical synthesis and loaded on antigen-presenting cells (APC), so that T cells are activated to identify various new antigen peptides, and the curative effect of killing the mutated tumor cells is further generated;
2. the antigen peptide related to liver cancer driver gene mutation obtained by screening has high affinity with MHC I molecules on DC cells, can effectively stimulate and induce to generate specific Cytotoxic T Lymphocytes (CTLs) and inhibit the growth of tumor cells, and has good potential of polypeptide vaccines and DC vaccines and good clinical transformation and disease prevention prospects.
Detailed Description
The invention will be further described with reference to specific embodiments:
the antigenic peptides related to mutations in the liver cancer driver genes used in the examples are shown in table 1:
TABLE 1 antigenic peptide sequences associated with mutations in the liver cancer driver gene
Figure BDA0003090571030000041
The operation of establishing the antigenic peptide specific CTL clone related to the liver cancer driving gene mutation is as follows:
10 of the same healthy donor5An individual CD8+T cell loading antigen peptide related to liver cancer driving gene mutation 1042 times of stimulation of Mo-DCs at intervals of 1 week and then 10 times of self-body5The mitomycin C treated PBMC loaded with the antigen peptide related to the liver cancer driver gene mutation is obtained by standard cytotoxic test screening after being stimulated for 1 time.
T2 cells were loaded with 5uM of the antigenic peptide associated with the mutation of the liver cancer driver gene as target cells, and the cytotoxic activity of CTL specific to the antigenic peptide associated with the mutation of the liver cancer driver gene was confirmed by LDH release assay.
Detection of LDH lactate dehydrogenase cytotoxicity:
1) the target cells were adjusted to 5X 10 with RPMI-1640 medium containing 5 vt% calf serum4-2×105/mL；
2) Target cells were added to 96-well round bottom cell culture plates at 100. mu.L per well. 3 effector cells are naturally released into control wells, no target cells are added, and only 100 mu L of culture solution is added;
3) add 100. mu.L of CTL effector cells (CD8+ T cells) to each well, with a ratio of effector cells to target cells of 10: 1; the natural release hole was filled with 100. mu.L of culture medium without effector cells, and 100. mu.L of 1 vt% NP40 was added to the maximum release hole. Each experiment is provided with three multiple wells;
4) placing at 37 ℃ for 5 vt% CO2Culturing for 4-6h in a carbon dioxide incubator;
5) centrifuging the culture plate for 200 Xg 10 min; sucking out 150 microliter of supernatant from each hole, and correspondingly adding the supernatant into another 96-hole enzyme-linked assay plate; to each well of the second plate were added 20. mu.L of a 0.4mol/L lactic acid solution, 20. mu.L of 4 mmol/L2-p-iodophenyl-3-p-chloronitrobenzenetetrazole, and 20. mu.L of a reaction solution (PB S containing 0.03 vt% BSA, 2.7U/mL lipoamide dehydrogenase, 4.5mmol/L hydrogenated coenzyme I (NAD +), 1.2 vt% sucrose) in this order, and the mixture was allowed to stand at room temperature for 20 min;
6) the optical density (OD value) of each well was measured on an enzyme-linked detector at a detection wavelength of 492nm and a reference wavelength of 650 nm.
The method for establishing antigen peptide specific CTL clone related to liver cancer driver gene mutation by adopting in vitro induction also establishes MHC-I restricted CTL clone, and the polypeptide specific immune response effect of the MHC-I restricted CTL clone is verified by IFN-gamma release experiments.
IFN- γ release assay:
1) coating antibody, taking 44 uL capture antibody and 12mL coat buff to dilute by 1:250 times, coating the liquid on a 96-well enzyme label plate by 100 uL per well, and standing overnight at 4 ℃;
2) washing the plate for 3 times, preparing washing liquor, adding 50mL of distilled water to prepare 1000mLwash buff, diluting by 1:20 times, and washing the plate for 3 times by using an automatic plate washing machine;
3) blocking 220 mu L of assay dilution in each hole and placing for 1h at room temperature;
4) washing the plate for 3 times;
5) prepare standard, dilute by equal ratio, and establish concentration gradient as blank well, 4.7pg/mL, 9.4pg/mL, 18.8pg/mL, 37.5pg/mL, 75pg/mL, 150pg/mL, 300pg/mL, respectively. And sequentially adding a sample to be detected, the auxiliary hole and the sample with overhigh concentration to be diluted. Standing at room temperature for 2 h;
6) washing the plate for 5 times;
7) preparing a detection antibody (secondary antibody) 48 mu L of detector antibody, adding 12mL of assay solution to prepare a solution, adding 48 mu L of SAV-HRP into the solution when adding the sample, and standing 100 mu L of each well at room temperature for 1 h;
8) washing the plate for 7 times;
9) adding chromogenic substrate streptomycin avidin peroxidase, keeping out of the sun for 30 min;
10) adding the stop solution, and carrying out colorimetric preparation on a standard curve by using 450nm as a measurement wavelength and 620nm as a reference wavelength on an enzyme-linked immunosorbent assay.
The results are shown in Table 2, and the results are absorbance values using PBS phosphate buffer and negative control peptide (control peptide sequence: AAAAAAAAA shown in SEQ ID NO. 18) as controls in the IFN-. gamma.release test data for the antigen peptides of SEQ ID NO.1-17, respectively. The experimental data show that the CTL epitope established by the invention is extremely effective, and the predicted result and the experimental result are very good in conformity.
TABLE 2 antigenic peptide IFN-. gamma.Release test results (absorbance values)
Serial number Antigenic peptides PBS control Negative control
SEQ No.1 482 30 35
SEQ No.2 469 28 39
SEQ No.3 478 29 38
SEQ No.4 168 29 37
SEQ No.5 476 28 36
SEQ No.6 182 29 35
SEQ No.7 478 32 38
SEQ No.8 485 32 37
SEQ No.9 483 32 36
SEQ No.10 469 32 35
SEQ No.11 468 32 34
SEQ No.12 467 32 35
SEQ No.13 465 32 36
SEQ No.14 471 30 37
SEQ No.15 472 30 38
SEQ No.16 480 33 41
SEQ No.17 477 32 40
Combining at least two antigenic peptides:
combination 1: SEQ ID NO.2, SEQ ID NO.7, SEQ ID NO.15 and SEQ ID NO. 17;
and (3) combination 2: SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.6, SEQ ID NO.11, SEQ ID NO.14 and SEQ ID NO. 15;
and (3) combination: SEQ ID NO.8 and SEQ ID NO. 13;
and (4) combination: SEQ ID NO.7, SEQ ID NO.14 and SEQ ID NO. 15;
and (3) combination 5: SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.8, SEQ ID NO.10, SEQ ID NO.13, SEQ ID NO.15 and SEQ ID NO. 16;
IFN-gamma release experiments were performed with the above five antigen peptide combinations, with PBS phosphate buffer and negative control peptide (control peptide sequence: AAAAAAAAA shown in SEQ ID NO. 18) as controls, and the results are absorbance values, as shown in Table 3.
TABLE 3 IFN-. gamma.Release test results (absorbance values) for antigen peptide combinations
Combination of Antigenic peptides PBS control Negative control
Combination 1 609±12 31±1 41±2
Combination 2 615±13 31±2 41±3
Combination 3 608±14 30±2 43±3
Combination 4 615±15 32±1 42±2
Combination 5 623±14 30±1 42±3
Therefore, at least two of the antigenic peptides related to the liver cancer driver gene mutation are subjected to dendritic cell presentation and cytotoxic lymphocyte T cell co-culture, so that the antigenic peptide specific cytotoxic T lymphocyte can be obtained through induction screening. The antigen specific cytotoxic T lymphocyte can be used for immune elimination of tumor cells with liver cancer related driver gene mutation, and prevention of related diseases, especially tumor diseases.
At least two of the antigen peptides and Dendritic Cells (DC) are loaded and returned for transfusion, and the antigen peptides can be used as DC vaccines for disease prevention, stimulate organisms to generate polypeptide specific anti-cytotoxic T cells related to liver cancer driver gene mutation, and further realize prevention of liver cancer driver gene mutation related diseases.
The antigen peptide related to liver cancer driver gene mutation has short length and small chemical synthesis difficulty, can be directly synthesized to obtain a high-purity product, greatly reduces the application cost, has definite effect and has good application potential.
Various other changes and modifications to the above-described embodiments and concepts will become apparent to those skilled in the art from the above description, and all such changes and modifications are intended to be included within the scope of the present invention as defined in the appended claims.
SEQUENCE LISTING
<110> Shenzhen City New Targeted Biotech Limited
<120> antigenic peptide related to liver cancer driver gene mutation and application thereof
<130> 2021
<160> 18
<170> PatentIn version 3.5
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Claims (6)

1. An antigenic peptide associated with mutations in liver cancer driver genes, wherein said liver cancer driver genes are at least two of CDKN2A, ERBB4, HNF1A, NFE2L2, NTRK3, LRP1B, PREX2, ZFHX3 and ZNF 521.
2. The antigenic peptides related to liver cancer driver gene mutation of claim 1, wherein the sequences of the antigenic peptides related to liver cancer driver gene mutation are at least two of SEQ No. 1-17.
3. Use of the antigenic peptide associated with mutations in the driver of liver cancer according to claim 1 for the induction of specific cytotoxic T cell clones.
4. Use of the antigenic peptide associated with mutations in the driver of liver cancer according to claim 1 for the preparation of a human immune activity modulator capable of inducing the generation of specific cytotoxic T cell clones.
5. Use of the antigenic peptide related to liver cancer driver gene mutation according to claim 1 for the preparation of a cell culture solution for the prevention and intervention of mutations in at least two genes selected from the group consisting of CDKN2A, ERBB4, HNF1A, NFE2L2, NTRK3, LRP1B, PREX2, ZFHX3 and ZNF 521.
6. The use of the antigenic peptide related to liver cancer driver gene mutation according to claim 1 in the preparation of a liver cancer risk intervention therapeutic agent.
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